Diagnosis of pyrimidine degradation disorder in patients with severe 5-FU side effect

• Project/Area Number: 16K18961
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Fujita Health University
• Principal Investigator: NAKAJIMA Yoko 藤田保健衛生大学, 医学部, 助教 (70598309)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: ピリミジン代謝異常症 / 尿中ピリミジン代謝物分析 / 5-フルオロウラシル / 薬物代謝スクスクリーニング / UPLC-MS/MS / DPD酵素活性測定 / 5-FU関連抗癌剤 / 薬物代謝スクリーニング検査 / 薬物代謝スクリーニング / 遺伝子検査 / 薬物動態代謝スクリーニング

Outline of Final Research Achievements

Pyrimidine degradation disorder was diagnosed using urine and blood sample from the patients who presented severe 5-FU side effect. Determination of pyrimidine and pyrimidine metabolite in urine was performed by UPLC-MS/MS. The diagnosis of dihydropyrimidine dehydrogenase(DPD) deficiency, dihydropyrimidinase(DHP) deficiency, β-ureidopropionase(βUP) deficiency, was made based on the pattern of the result of pyrimidine metabolite analysis. The stable method of DPD activity in peripheral blood mononuclear cells (PBMC) was established. Decreased DPD activity of 20% of control was detected in the patients with normal urinary pyrimidine metabolite analysis.
Our procedure of screening test for pyrimidine degradation disorders was successfully worked so it is expected to expanding screening test before 5-FU administration.

Research Products

• [Journal Article] Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity. (2017)
  • Author(s): Nakajima Y, Meijer J, Dobritzsch D, Ito T, Zhang C, Wang X, Watanabe Y, Tashiro K, Meinsma R, Roelofsen J, Zoetekouw L, van Kuilenburg ABP
  • Journal Title: Molecular genetics and metabolism Volume: 122 Pages: 216-222
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Japanese case of β-ureidopropionase deficiency with dysmorphic features (2017)
  • Author(s): Akiyama, T., Shibata, T., Yoshinaga, H., Kuhara, T., Nakajima, Y., Kato, T., Maeda, Y., Ohse, M., Oka, M., Kageyama, M., Kobayashi, K.
  • Journal Title: Brain and Development Volume: 39 Issue: 1 Pages: 58-61
  • DOI: 10.1016/j.braindev.2016.08.001
  • Peer Reviewed / Open Access